Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer

Medhi Wangpaichitr, Chunjing Wu, Ying Ying Li, Dan J.M. Nguyen, Hande Kandemir, Sumedh Shah, Shumei Chen, Lynn G. Feun, Jeffrey S. Prince, Macus T. Kuo, Niramol Savaraj

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD + (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD + re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

Original languageEnglish
Pages (from-to)49275-49292
Number of pages18
JournalOncotarget
Volume8
Issue number30
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

Riluzole
Cisplatin
Reactive Oxygen Species
Lung Neoplasms
Glutamine
NAD
Antiporters
Glutathione
Glutamic Acid
Motor Neuron Disease
Pharmaceutical Preparations
Oxidative Stress
Cell Death
lactate dehydrogenase 5
Therapeutics

Keywords

  • Lung cancer
  • Oxidative metabolism
  • Reactive oxygen species
  • Resistance
  • Riluzole

ASJC Scopus subject areas

  • Oncology

Cite this

Wangpaichitr, M., Wu, C., Li, Y. Y., Nguyen, D. J. M., Kandemir, H., Shah, S., ... Savaraj, N. (2017). Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. Oncotarget, 8(30), 49275-49292. https://doi.org/10.18632/oncotarget.17568

Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. / Wangpaichitr, Medhi; Wu, Chunjing; Li, Ying Ying; Nguyen, Dan J.M.; Kandemir, Hande; Shah, Sumedh; Chen, Shumei; Feun, Lynn G.; Prince, Jeffrey S.; Kuo, Macus T.; Savaraj, Niramol.

In: Oncotarget, Vol. 8, No. 30, 01.01.2017, p. 49275-49292.

Research output: Contribution to journalArticle

Wangpaichitr, M, Wu, C, Li, YY, Nguyen, DJM, Kandemir, H, Shah, S, Chen, S, Feun, LG, Prince, JS, Kuo, MT & Savaraj, N 2017, 'Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer', Oncotarget, vol. 8, no. 30, pp. 49275-49292. https://doi.org/10.18632/oncotarget.17568
Wangpaichitr M, Wu C, Li YY, Nguyen DJM, Kandemir H, Shah S et al. Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. Oncotarget. 2017 Jan 1;8(30):49275-49292. https://doi.org/10.18632/oncotarget.17568
Wangpaichitr, Medhi ; Wu, Chunjing ; Li, Ying Ying ; Nguyen, Dan J.M. ; Kandemir, Hande ; Shah, Sumedh ; Chen, Shumei ; Feun, Lynn G. ; Prince, Jeffrey S. ; Kuo, Macus T. ; Savaraj, Niramol. / Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer. In: Oncotarget. 2017 ; Vol. 8, No. 30. pp. 49275-49292.
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